Combination therapy

Abstract

The present invention provides a therapeutic combination for use in treating an infection with a pathogen. The therapeutic combination comprises an aminoglycoside antibiotic; and a nucleic acid monoalkylating agent that substitutes a single nucleotide of a nucleic acid with an alkyl group, wherein the therapeutic combination provides an enhanced suppression of a pathogen when compared with an otherwise identical composition lacking said aminoglycoside antibiotic; or wherein the therapeutic combination provides an enhanced suppression of a pathogen when compared with an otherwise identical composition lacking said nucleic acid monoalkylating agent; and kits for performing said method.

The invention claimed is: 
     
       1. A method of suppressing, reducing or removing an infection with a pathogen in a subject, said method comprising administering a therapeutic combination to the subject, wherein said therapeutic combination comprises:
 a. an aminoglycoside antibiotic; and 
 b. a nucleic acid monoalkylating agent that substitutes a single nucleotide of a nucleic acid with an alkyl group;
 wherein the therapeutic combination provides an enhanced suppression of a pathogen when compared with an otherwise identical composition lacking said aminoglycoside antibiotic; or 
 wherein the therapeutic combination provides an enhanced suppression of a pathogen when compared with an otherwise identical composition lacking said nucleic acid monoalkylating agent. 
 
 
     
     
       2. The method according to  claim 1 , wherein said aminoglycoside antibiotic is administered prior to, simultaneously with or sequentially to said nucleic acid monoalkylating agent. 
     
     
       3. The method according to  claim 1 , wherein said pathogen is a bacterium. 
     
     
       4. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that removes an alkyl group from an alkylated nucleotide adduct. 
     
     
       5. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that removes an alkyl group from an alkylated nucleotide adduct; and wherein said alkylated nucleotide adduct is one or more selected from 3meC, 3meG, 3meA, 8-oxo-G, O2-alkylthymine, O4-alkylthymine, O6-methylguanine, and O6-ethylguanine. 
     
     
       6. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that removes an alkyl group from an alkylated nucleotide adduct; and wherein said gene is one or more selected from alkA and alkB. 
     
     
       7. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that promotes tolerance of a cell to the presence of an alkylated nucleotide adduct within a nucleic acid of the cell. 
     
     
       8. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that promotes tolerance of a cell to the presence of an alkylated nucleotide adduct within a nucleic acid of the cell; and wherein said one or more gene is selected from Ada, OGT, RecA, DinB, and UmuCD. 
     
     
       9. The method according to  claim 1 , wherein said pathogen is one or more selected from a  Salmonella  bacterium, a  Pseudomonas  bacterium, and a  Mycobacterium  bacterium. 
     
     
       10. The method according to  claim 1 , wherein said aminoglycoside antibiotic is one or more selected from kanamycin, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin, and streptomycin, or a salt thereof. 
     
     
       11. The method according to  claim 1 , wherein said aminoglycoside antibiotic is kanamycin. 
     
     
       12. The method according to  claim 1 , wherein said nucleic acid monoalkylating agent is one or more selected from N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS), dacarbazine, methylnitrosourea (MMU), ethyl methanesulfonate (EMS), temozolomide (TMZ), ethylnitrosourea (ENU), diethyl nitrosamine (DEN), and N-Nitroso-N-methylurea (NMU). 
     
     
       13. The method according to  claim 1 , wherein said nucleic acid monoalkylating agent is methyl methanesulfonate (MMS). 
     
     
       14. The method according to  claim 1 , wherein said nucleic acid monoalkylating agent substitutes a nucleotide of a nucleic acid with an alkyl group to provide one or more alkylated nucleotide adduct selected from 3meC, 3meG, 3meA, 8-oxo-G, O2-alkylthymine, O4-alkylthymine, O6-methylguanine, and O6-ethylguanine. 
     
     
       15. A method of in vitro disinfection, the method comprising applying an agent combination at a site comprising a pathogen, a site suspected of comprising a pathogen, or at a site at risk of comprising a pathogen, wherein said agent combination comprises:
 a. an aminoglycoside antibiotic; and 
 b. a nucleic acid monoalkylating agent that substitutes a single nucleotide of a nucleic acid with an alkyl group; 
 wherein the agent combination provides an enhanced suppression of a pathogen when compared with an otherwise identical composition lacking said aminoglycoside antibiotic; or 
 wherein the agent combination provides an enhanced suppression of a pathogen when compared with an otherwise identical composition lacking said nucleic acid monoalkylating agent. 
 
     
     
       16. The method according to  claim 15 , wherein said applying comprises providing a local concentration of said aminoglycoside antibiotic and said nucleic acid monoalkylating agent at said site of about 1 mM to about 200 mM. 
     
     
       17. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that removes an alkyl group from an alkylated nucleotide adduct; and wherein said gene is alkB. 
     
     
       18. The method according to  claim 1 , wherein said pathogen lacks one or more gene encoding a polypeptide that promotes tolerance of a cell to the presence of an alkylated nucleotide adduct within a nucleic acid of the cell; and wherein said alkylated nucleotide adduct is one or more selected from 3meC, 3meG, 3meA, 8-oxo-G, O2-alkylthymine, O4-alkylthymine, O6-methylguanine, and O6-ethylguanine. 
     
     
       19. The method according to  claim 15 , wherein said applying comprises providing:
 a. a local concentration of said aminoglycoside antibiotic of about 80 mM to about 120 mM; and/or 
 b. a local concentration of said nucleic acid monoalkylating agent of about 1 mM to about 40 mM.